As precursors of reactive quinone methides, many natural and synthetic quinones function as bioreductive alkylating agents and have antitumor activity. (See for example, Thomson R H, Naturally occuring quinones III: recent advances. New York: Chapman and Hall 1987; Moore H W, Science 1977, 197: 527-32; Lin A J, et al, J Med Chem 1972, 15: 1247-52; Lin A J, et al, J Med Chem 1973, 16: 1268-71; Lin A J, et al, J Med Chem 1974, 17: 558-61; Lin A J, et al, J Med Chem 1975, 18: 917-21). The cytotoxicity of quinones may be due to two competing mechanisms: soft electrophilic arylation and redox cycling oxidation. (See for example, Brunmark A, Cadenas E, Free Radical Biol Med 1989, 7:435-77; O""Brien P J, Chem-Biol Interact 1991, 80: 1-41; Monks T J, et al, Toxicol Appl Pharmacol 1992, 112: 2-16). While complete two-electron reduction of the quinone ring by DT diaphorase produces a stable hydroquinone, partial one-electron reduction of the quinone ring by NADPH-oxidizing enzymes yields an unstable semiquinone free radical (FR) that can spontaneously autoxidize at the expense of molecular O2 to generate a cascade of reactive O2 species (ROS) and FRs, which can induce DNA damage, lipid peroxidation and cytotoxicity. However, most quinone antitumor agents used clinically, such as anthracycline antibiotics, mitomycin C and benzoquinone derivatives, have a complex chemical structure with a number of active functional groups and the exact contribution of the quinone group to their antitumor activity remains uncertain. (See for example, Myers C E, Chabner B A, Anthracyclines. In: Chabner B A, Collins J M, eds. Cancer chemotherapy: principles and practice. Philadelphia: Lippincott 1990: 356-81; Rossi L, et al, Arch Biochem Biophys 1986, 251: 25-35; Begleiter A, et al, Cancer Res 1988, 48: 1727-35; Qiu X B, et al, Free Radical Biol Med 1998, 24: 848-54). The anthracycline quinone antibiotics adriamycin (ADR) and daunomycin (DAU) covalently bind to and intercalate into DNA, inhibit DNA replication and RNA transcription, are DNA topoisomerase (Topo) II poisons, produce oxidative stress and damage biomembranes, induce DNA breakage and chromosomal aberrations, trigger apoptosis and have a wide spectrum of anticancer activity. (See for example, Cadenas E, Free Radical Biol Med 1998, 24: 848-54; Liu L F, Annu Rev Biochem 1989, 58: 351-75; Mimnaugh E G, et al, Cancer Res 1985, 45: 3296-304; Ganapathi R, et al, Biochem Pharmacol 1990, 40: 1657-62; Ling Y-H, et al, Cancer Res 1993, 53: 1845-52; Ramachandran C, et al, Anticancer Res 1997, 17: 3369-76). However, the clinical effectiveness of DOX and DAU is severely limited by their cumulative cardiotoxicity and ability to induce multi-drug resistance, so it is important to develop drugs with improved bioactivity.
This invention provides analogs of triptycene which are useful as anticancer drugs, as well as for other uses. The potency of these compounds is in a similar magnitude as daunomycin, a currently used anticancer drug. Each compound of the invention produces one or more desired effects (blocking nucleoside transport, inhibiting nucleic acid or protein syntheses, decreasing the proliferation and viability of cancer cells, inducing DNA fragmentation or retaining their effectiveness against multidrug-resistant tumor cells).
More specifically, the invention provides triptycene analogs having the following formula: 
wherein X is selected from the group consisting of: H, R, SR and NR2;
Y is selected from the group consisting of: halogen (preferably Cl, Br, I), R, NR2, SR and H;
R and R1-2 are independently selected from the group consisting of: H, halogen, OR, and hydrocarbyl (preferably lower alkyl, allyl, phenyl, aryl, substituted alkyl, substituted allyl, substituted phenyl, xe2x80x94CH2xe2x80x94(CH2)nCO2H, xe2x80x94CH2xe2x80x94(CH2)nCH(NH2)CO2H, carboxylic acid, substituted carboxylic acid, amine, substituted amine, NHR, NR2, amino acid, RCO2(CH2)nNH, where one or both of the hydrogen atoms on CH2 can be substituted with alkyl, allyl, phenyl, aryl, substituted allyl, substituted phenyl, substituted carboxylic acid, amine, or substituted amine, and where n is an integer from 0 to 8); R3-4, independently of one another, are selected from the group consisting of: H, halogen (preferably bromine), OR, R, SR and NR2; R5, independently of other R5s, is selected from the group consisting of: xe2x95x90O, xe2x95x90Nxe2x80x94OH, and xe2x95x90CHR; and reduced forms thereof; wherein in reduced forms, either ring A or ring C or both is replaced with 
and wherein in reduced forms, each R5 is independently H, C1-C8 alkyl or xe2x80x94OR;
and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
The numbering scheme used herein is shown in the example structure below: 
Other compounds of the invention include those with formula: 
wherein
R5 is selected from the group consisting of: R, halogen, NR2, SR and H; R6 is selected from the group consisting of: H, R, SR and NR2; R7 and R8 are independently selected from the group consisting of: H, halogen, OR and hydrocarbyl; R17 and R18 are independently selected from the group consisting of: H, halogen, (preferably bromine), R, SR and NR2; R19 and R20 are, independently of one another, H, R, or OR; (R9 and R10) and (R11 and R12) and (R13 and R14) and (R15 and R16) are together xe2x95x90O or are independently H or xe2x80x94OR; R is selected from the group consisting of H, halogen, OR and hydrocarbyl; reduced forms thereof and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Other compounds of the invention include those with formula: 
wherein X is xe2x80x94NW(CW2)nZ, where the Ws are independently selected from the group consisting of: H, C1-C8 alkyl, and C1-C8 alkenyl and Z is selected from the group consisting of: R, COR, COOR, CONR2, OOCR and NRCOR;
Y is selected from the group consisting of: halogen, C1-C8 alkyl, C1-C8 alkenyl, OR, NR2, SR, H, COR, OCOR and NRCOR;
R and R1-2 , are independently selected from the group consisting of: H, OR, and hydrocarbyl;
R3-4, independently of one another, are selected from the group consisting of: H, OR, SR, and NR2;
R5, independently of other R5s, is selected from the group consisting of: xe2x95x90O, xe2x80x94H and xe2x80x94OT, where T is H or C1-C8 alkyl or alkenyl; and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Other compounds of the invention include those with formula: 
wherein X is selected from the group consisting of: H, R; SR and NR2;
Y is selected from the group consisting of: halogen, NR2, SR, H, and R;
R and R1-2, are independently selected from the group consisting of: H, halogen, OR, and hydrocarbyl;
R3-4, independently of one another, are selected from the group consisting of: H, halogen (preferably bromine), R, SR, and NR2;
R5, independently of other R5s, is selected from the group consisting of: xe2x95x90O, xe2x95x90NOH, xe2x95x90C HR and reduced forms thereof;
R21 and R22 are independently selected from the group consisting of: H, R, and OR; and reduced forms thereof and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Also provided are compounds of the formula: 
and the reduced forms thereof, wherein in said reduced forms, either ring A or ring C or both is reduced to 
wherein all but one of X, Y, R1 and R2 is independently H, C1-C6 alkyl, C1-C6 alkenyl, OR, SR or NR2 wherein each R is independently H or C1-C6 alkyl and the other R1 or R2 is a solubilzing group; and each R5 is independently H, C1-C6 alkyl or OR. The solubilizing group may be of the formula: NR(CR2)nX wherein X is a sugar, R, COR, COOR, CONR2, OOCR and NRCOR; R is independently selected from the group consisting of: H, C1-C8 alkyl and C1-C8 alkenyl; n is an integer from 1 to 8.
Scheme 1 shows some of the compounds of the invention and abbreviations used herein. 
Currently, the most preferred compounds include those compounds of the formulas listed above wherein at least one of X, Y, R1 and R2 is selected from the group consisting of: a nitrogen containing group, a water soluble group, and a sulfur containing group, and the following: 
The compounds listed above are useful in treating malaria, cancer, as well as other diseases. Other preferred compounds include those specifically depicted and described in this disclosure.
A class of compounds of this invention includes those compounds listed above as presently preferred. Another class of compounds of this invention include TT2 and TT13. Another class of compounds of this invention include TT1, TT7 and TT9. Another class of compounds of this invention include one or members of the class TT3, TT5, TT6, TT8 and TT10. Another class of compounds of this invention includes homologs of the foregoing compounds. One class of compounds is the compounds TT1-13. Another class of compounds is TT14-20. One class of compounds are those where X is selected from the group consisting of: H, OMe and CO2Me; where Y is selected from the group consisting of: H, Br, and OMe; where R1xe2x95x90R2xe2x95x90H; and where positions 1, 4, 5 and 8 are selected from the group OH, OMe, xe2x95x90O, H. Another class of compounds include those where one or more substituents contains one or more N atoms. Another class of compounds includes those where X and Y are not both members of the group containing: H, OMe, Br, CO2 Me, while positions 1, 4, 5, and 8 are substituted with xe2x80x94OH, xe2x80x94OMe or xe2x95x90O, or mixtures of those substituents. Another class of compounds include those which include at least one amine, amino acid or amine sugar substituent.
A preferred class of compounds is those which are water soluble, where one or more substituents, particularly where X,Y,R1 and/or R2 substituents of formula I are replaced with water soluble group or groups that enhance the solubility of the compound and salts thereof.
A preferred class are those compounds of formula I where X is a water soluble group or a group that enhances the water solubility of the compound; and salts thereof. These compounds include those where X is RO2C (CH2)nNH, where n is an integer from 1 to 8 and R is as defined for I.
Another class of compounds includes those that contain a sulfur containing substituent.
This invention also provides methods for inhibiting cellular transport of nucleosides; inducing DNA fragmentation; inhibiting nucleic acid and/or protein synthesis and decreasing the proliferation and viability of cancer cells (including wild type and multi-drug resistant) or other cells in which the proliferation or viability is desired to be reduced, comprising contacting the cells with an effective amount of a compound of the invention as disclosed herein. This invention provides such compounds in suitable pharmaceutical carriers in dosages effective to provide measurable nucleoside transport blocking, nucleic acid and/or protein synthesis inhibition, DNA cleavage, and/or reduction in tumor cell (including wild type and multi-drug resistant) growth and/or viability. Preferably, the compounds used in the methods of this invention are almost or at least as effective as Daunomycin, a currently used anticancer drug.
Also provided is a method of treating cancer in a host, comprising: administering to said host an effective amount of an active compound of the invention for an effective time. Administration routes include intravenously, parenterally, and other methods known in the art. As used herein, an xe2x80x9ceffective amountxe2x80x9d is an amount which causes a measurable effect on a desired parameter. As used herein, an xe2x80x9ceffective timexe2x80x9d is the time required to cause a measurable or desired effect on a desired parameter.
Also provided is a method for preparation of triptycene analogs, comprising in situ oxidation and [4+2] cycloaddition of substituted benzenes or quinones and optionally substituted anthracenes; and optional oxidation of the resulting compounds. The resulting compounds will be a mixture of methoxy-substituted and carbonyl-substituted triptycene analogs. This mixture can be separated into individual compounds with methods known in the art. The one pot synthesis may be separated into oxidation and cycloaddition steps, if desired. Synthesis of particular groups of compounds of the invention are described in more detail herein.
Also provided is a method to synthesize 1,4-dimethoxyanthracene comprising reduction of quinizarin to give 1,4-anthraquinone; reduction of 1,4-anthraquinone to give 1,4-dihydroxyanthracene; and methylation of 1,4-dihydroxyanthracene to give 1,4-dimethoxyanthracene. These reactions are described in more detail herein. The reduction step (first step; with sodium borohydride) has been reported in: Bedworth, P. V.; Perry, J. W.; Marder, S. R. J. Chem. Soc. Chem. Commun. 1997, 1353-1354 for use in certain synthetic methods and the following two steps (reduction with sodium hydrosulfite and methylation) have been used in certain syntheses, but preparation of 1,4-dimethoxyanthracene (1) has not been reported in one sequence of reaction.
A new synthesis of the compound TT2 is also provided. Either TT3, TT5 or a mixture of both is oxidized to give TT2. A new method to brominate triptycene analogs is also provided. Treatment of a triptycene analog which has a methoxy group on position 2 and a hydrogen on position 3 with N-bromosuccinimide gives an analog with a bromine on position 3. This bromination reaction can be extended to other triptycene analogs. For example, if a methoxy group is on position 6 or 7, bromination will result in a bromine on position 7 or 6, respectively. If the starting compound has methoxy groups on positions 5 and 6, oxidation will give the corresponding analog with carbonyl groups on positions 5 and 6.
Triptycene analogs I bearing functionalities at C12 and C13 (R3 and R4), can be made in an analogous reaction as described below starting with 6,7-disubstituted 1,4-dimethoxyanthracenes (analogs of compound 1). These 6,7-disubstituted 1,4-dimethoxyanthracenes are prepared from the corresponding analogs of 6,7-disubstituted 1,4-dihydroxy-9,10-anthraquinones (by following the method described below).
Also provided are triptycene analogs prepared by the methods described herein.
Compounds containing any combination of substituents or members of the Markush groups specified above are within the scope of the invention. All substituents of the compounds of the invention may be the same, all substituents may be different, or any combination of substituents may be the same or different. Compounds having substituents with a specified function, for example those that impart water solubility to the compound form a special class of compounds of this invention.
The substituents included in the compounds of the invention and used in the methods of the invention may be any substituent not having structures or reactivity which would substantially interfere with the desired activity of the compound, as may readily be determined without undue experimentation by those skilled in the art, for example, by using the assay methods disclosed herein and those methods known to one of ordinary skill in the art.
The reduced forms of all compounds described herein are included in the disclosure. It is understood that when referring to reduced forms of structures herein, any quinone-like ring of the structure may be replaced with a hydroquinone-like ring, as known in the art.
For example, in the following structure, 
in reduced forms, either ring A or ring C or both is replaced with 
wherein in reduced forms, each R5 is independently a reduced form of xe2x95x90O, for example, OR. In the reduced forms, each R5 may also be H or C1-C8 alkyl, for example, as known in the art.